The present invention relates to a pharmaceutical composition comprising pharmaceutically active amounts of galanin, octreotide and serotonin, respectively, and a pharmaceutically acceptable carrier. Also said composition comprising galanin, octreotide and serotonin, for medical use is disclosed. A method for treating a human or non-human animal with a disorder, or may potentially be affected by a disorder, associated with neoplastic cells, comprising the step of administering an above composition is also disclosed.
Colorectal cancer is a major cause of morbidity and mortality in non-smokers in the western world, with 300,000 new cases diagnosed in Europe and in the USA each year (Midgely and Kerr, 1999). Around 50% of these patients develop metastatic disease after surgical resection of the primary tumour, or it may be initially present with advanced disease (Berger et al, 1973). Colorectal carcinoma is relatively resistant to chemotherapy, and radiation therapy is usually used only for palliative purposes (Valone et al., 1987; Muhiuddin and Karks, 1991).
The neuroendocrine peptides and amines of the gut play a significant role in regulating the proliferation and growth of gastrointestinal epithelial and mesenchymal cells (Hill, 1991). These bioactive substances are also involved in regulating the local immune defence of the gut (O""Dorisio, 1987). Both cell proliferation and local immune defence of the gut are important in the development and growth of colorectal cancer. It was speculated that there might be an abnormality in the neuroendocrine system in the colon of patients with colon carcinoma that might initiate and/or promote the development of the colorectal carcinoma (E1-Salhy et al., 1998a). In support of this assumption is the finding of low levels of somatostatin and galanin, and decreased cell density of somatostatin and serotonin in the colon of patients with colon carcinoma (E1-Salhy et al, 1998a; 1988b). Furthermore, the number of colonic somatostatin and serotouni cells was restored in patients with rectal carcinoma that received pre-operative radiotherapy (E1-Salhy et al., 1988c). As pre-operative radiotherapy has been found to improve 5- and 10-year survival rates and to reduce local recurrences, it would seem that restoring the number of these endocrine cells in these patients plays a role in improving their prognosis.
There is however still a need for new compositions and methods for therapy for treating disorders associated with neoplastic cells, e.g. colorectal cancer.
The present invention, which solves the above problem, relates to a pharmaceutical composition comprising pharmaceutically active amounts of galanin, octreotide and serotonin, respectively, and a pharmaceutically acceptable carrier. Further a composition comprising galanin, octreotide and serotonin, for medical use is claimed. A method for treating a human or non-human animal with a disorder, or may potentially be affected by a disorder, associated with neoplastic cells, comprising the step of administering a composition as set out above is also disclosed.
The pharmaceutically active components octreotide (which is a somatostatin analogue), galanin, and serotonin may be used in derivatized form or analogues thereof may be used as well. The above components may further be used in their salt forms.
According to one preferred embodiment of the present invention, the pharmaceutical composition, as set out in the present description, comprising pharmaceutically active amounts of galanin, octreotide and serotonin, respectively, and a pharmaceutically acceptable carrier provides an active dose lies in the range of from about 10 xcexcg/kg body weight to about 60 xcexcg/kg body weight of galanin, octreotide and serotonin, respectively; preferably about 10 xcexcg/kg to about 20 xcexcg/kg of galanin, octreotide and serotonin, respectively.
The expression xe2x80x9cpharmaceutically acceptablexe2x80x9d is meant to include in the present description ingredients that are compatible with other ingredients of the compositions as well as physiologically acceptable to the recipient, e.g. a human, without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like. Compositions for use according to the present invention may comprise one or more carriers, excipients and/or diluents as set out below.
According to one preferred embodiment of the present invention there is provided use of a composition as set out above in the preparation of a medicament for the treatment, profylaxis or management of a disorder associated with neoplatic cells.
According to one preferred embodiment of the present invention there is provided a method for treating a human or non-human animal with a disorder, or may potentially be affected by a disorder, associated with neoplastic cells comprising the step of administering a composition comprising galanin, octreotide and serotonin. The disorder associated with neoplastic cells may e.g. be colorectal cancer, gastric cancer, prostate cancer, cancer in the pancreas. Preferably the disorder is colorectal cancer. Preferably the active dose lies in the range of from about 10 xcexcg/kg body weight to about 60 xcexcg/kg body weight of galanin, octreotide and serotonin, respectively; preferably about 10 xcexcg/kg to about 20 xcexcg/kg of galanin, octreotide and serotonin, respectively.
Non-human animals which may be treated preferably include mammals, particularly livestock and domestic animals such as dogs, cats, rabbits, guinea pigs, hamsters, mice, rats, horses, goats, sheep, pigs and cows.
Depending on the mode of administration, various forms of the compositions may be used. Thus, pharmaceutical compositions may be formulated in conventional manner using readily available ingredients. The active ingredients i.e. galanin, octreotide and serotonin may be incorporated, optionally together with other active substances, with one or more conventional carriers, diluents and/or excipients, to produce conventional galanic preparations such as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatine capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
Examples of suitable carriers, excipients and diluents, are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacant, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, water, water/ethanol, water/glycol, water/polyethylene glycol, propylene glycol, methyl cellulose, methylhydroxybenzoates, propyl hydroxybenzoates, talc, magnesium stearate, mineral oil or fatty substances such as hard fat or suitable mixtures thereof. The compositions may additionally include lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavouring agents, and the like. The compositions of the intention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Compositions may be in an appropriate dosage form, for example as an emulsion or in liposomes, niosomes, microspheres, nanoparticles or the like. If the target disorder is not present in the stomach, the composition comprising galanin, octreotide and serotonin according to the present invention and the composition is taken orally, said composition is enterically coated for passage through the stomach; enteric coatings as such are well known in the art. Examples of enteric coating polymers are cellulose acetate phtalate, hydroxy propyl methyl cellulose phtalate, polyvinyl acetate phtalate carboxy metyl ethyl cellulose, co-polymerized methacrylic acid and methacrylic acid/methacrylic acid methyl esters such as compounds known under the trade name Eudragit (Rxc3x6hm Pharma).
If required, the compositions may also contain targeting moieties attached to the active ingredient, e.g. a ligand which binds specifically and selectively to an endogenous receptor to allow targeting to a particular cell type or location, such as targeting to certain specific e.g. vitally affected cells. Thus an even more targeted action may be accomplished.
Administration may be performed by local or systemic application as appropriate.
Administration of compositions for use in the invention may take place by, any of the conventional routes, e.g. by inhalation, orally, rectally or parenteraUy, such as by intramuscular, subcutaneous, intraarticular, intracranial, intradermal, intraocular, intraperitoneal, intrathecal, intravenous injection although this depends on the condition to be treated. The injection may even be performed directly into an affected locus (for example, by stereotaxic injection). Local administration may also be performed, e.g. at an affected site e.g. by use of a catheter or syringe. Treatment by topical application of a composition, e.g. an ointment, to the skin is also possible for appropriate conditions. Optionally administration may be performed at intervals, e.g. 2 or more applications, e.g. 2-4 applications at hourly, daily, weekly or monthly intervals, e.g. several times a day, or every 3-5 days, or at fortnightly, monthly or quarterly intervals.
The active ingredients i.e. galanin, octreotide and serotonin in compositions used in the invention may be comprised from about 0.01% to about 99% by weight of the formulation, preferably from about 0.1 to about 50%, for example 10%. The compositions may preferably be formulated in a unit dosage form, e.g. with each dosage containing from about 0.01 mg to about 1 g of the active ingredient, e.g. 0.05 mg to 0.5 g, for a human, e.g. 1-100 mg. The precise dosage of the active compound to be administered and the length of the course of treatment will, of course, depend on a number of factors including for example, the age and weight of the patient, the specific condition requiring treatment and its severity, and the route of administration. Generally however, an effective dose may lie in the range of from about 10 xcexcg/kg body weight to about 60 xcexcg/kg body weight of galanin, octreotide and serotoin, preferably about 10 xcexcg/kg to about 20 xcexcg/kg of galanin, octreotide and serotonin, respectively, per day, depending on the animal to be treated and the dosage form, taken as a single dose. Thus for example, an appropriate daily dose for an adult may be from 0.5 mg to 2 g per day, e.g. 1.0 to 500 mg of galanin, octreotide and serotoi respectively, per day.
As noted above, the present invention provides a variety of pharmaceutical compositions, such as also vaccine compositions against neoplastic cells.
We will now describe the present invention by using Figures and Examples but they are only for purposes of illustration and shall not in any way limit the scope of the appended set of claims.